Finding Oxidation

Imagine for a second that you’re a scientist studying chemical reactions in a cell. Imagine you want to study one specific reaction and you develop a chemical that can bind to all of the spots where this reaction occurs.

Here’s the problem. Cells have been evolving for billions of years, and all of that evolution has made them very good at chemistry. If your molecule can’t react quickly enough, it won’t be able to compete with the cell’s normal activity, and you won’t be able to study your reaction.

Bruce King, Ph.D., and Thomas Poole, two chemists at Wake Forest University, recently tackled such a problem. They developed a new molecule to study their reaction that works 300 times faster than the molecule currently used to study the reaction.

King and Poole were studying reactions involving a compound called protein sulfenic acid, an important indicator of oxidation in cells. In normal circumstances, oxidation is beneficial for cell functions. Oxygen compounds like peroxide and superoxide react with certain proteins to make protein sulfenic acids, and they, in turn, fine-tune the functions of enzymes.

In high quantities, these so-called reactive oxygen species can have catastrophic effects on cells and even cause some forms of cancer in humans. They are so highly reactive that they can ruin enzymes and tear apart DNA. In fact, when oxygen first started to build up in the atmosphere, it caused a mass extinction, wiping out any organisms that couldn’t protect themselves.

Since protein sulfenic acids are indicators of cellular oxidation, monitoring where and how these compounds react could be important for future research into oxidation-related cancers.

King and Poole’s molecule is in the family of bicyclononynes (BCNs), and if you break down the name, it tells you a few things: Bi (two) – cyclo (rings) – non (nine carbon atoms) – yne (a triple bond). King and Poole’s BCNs have some extra stuff attached, but this part always stays the same.

You can see in the picture that the octagon and the triangle are the two rings where each corner is a carbon for a total of nine. Each line is a chemical bond, and the triple line is a triple bond.

The secret to BCN's effectiveness is in that triple bond and ring combo. According to something called valence shell electron pair repulsion (VSEPR) theory – a long string of big words that essentially say electrons in chemical bonds will repel each other until a molecule reaches a specific shape – says that you shouldn’t be able to put a triple bond in a ring.

The thinking goes something like this: a chemical bond is really a pair of electrons that two atoms share. A double bond is two pairs. A triple, three. All electrons have a negative charge so when an atom has more than one bond, the negative charges repel each other and the bonds try to move as far away from each other as possible. An atom with two bonds will keep those bonds 180 degrees from each other.

That’s the case for each of the carbon atoms involved in the triple bond – in VSEPR theory a triple bond counts as one bond because all three pairs of electrons are shared with the one other atom. So each of these atoms wants to keep the triple bond and the single bond 180 degrees from each other like in this picture of hydrogen cyanide. But in the BCN ring, the bonds aren’t 180 degrees from each other. In order to make the ring work, they’re closer to 135 degrees apart.

VSEPR theory isn’t law, and the rules have a little wiggle room, but molecules that disobey aren’t happy about it. It’s a lot like being crammed into the back seat of a convertible. It’s got a real seat and a seatbelt and you can get away with riding there, but as soon as you can, you’re going to get out and stretch your legs.

Ringed chemicals that similarly need to stretch their electron legs are said to have ring strain and the more strain a molecule is under, the more quickly it will react.

As soon as that BCN’s triple bond runs into a protein sulfenic acid, the carbons rush to bond to the acid, leaving a permanent attachment to sulfenic acid and a more ring-friendly double bond in the ring. Then, King and Poole can track down the BCN and find where these sulfenic acids are working.